Fentanyl and its analgetically effective derivatives (hereafter referred to as "derivatives") such as sufentanyl, carfentanyl, lofentanyl and alfentanyl have long been known as extremely potent and effective anesthetics and analgesics. Fentanyl is described in U.S. Pat. No. 3,164,600 and its use as approved by the FDA in the United States is described in the 1984 Physician's Desk Reference, pages 1027 through 1029 with reference to the drug SUBLIMAZE.RTM. manufactured by McNeil Lab for Janssen Pharmaceutica, Inc. In use, fentanyl is normally administered as the citrate either as a bolus injection or infusion or a continuous infusion for the purposes of producing anesthesia or analgesia.
The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this are disclosed in numerous technical journals and patents. U.S. Pat. Nos. 3,598,122, 4,144,317, 4,201,211, 4,262,003, and 4,379,454, all of which are incorporated herein by reference, are representative of various transdermal drug delivery systems of the prior art, which systems have the ability of delivering controlled amounts of drugs to patients for extended periods of time ranging in duration from several hours to several days. None of the above patents nor any other prior art of which the inventors are aware describes a transdermal delivery system which is intended to deliver fentanyl or its derivatives nor are they aware of data on skin permeability or therapeutic transdermal delivery rates adequate to design such a system. Furthermore, fentanyl and its derivatives have certain unique characteristics which impose a combination of restraints on a transdermal delivery system which have hitherto not been addressed in other systems.
Fentanyl and its derivatives are highly potent, rapidly metabolized drugs having a relatively narrow therapeutic index which produce extremely undesirable side effects on overdosage, most notably respiratory depression, which if left unchecked can cause death. They are also relatively expensive and have a high potential for abuse. We have found that these characteristics impose numerous and sometimes conflicting design constraints on a practical transdermal delivery device. For example, it would be desirable that the device deliver the drug at a substantially constant rate for at least about 24 hours while at the same time keeping the amount of drug within both the unused and depleted systems to a minimum. Another example of conflicting constraints is that the degree to which the system controls the release rate should be relatively high in order to assure that excessive amounts of the drug are not delivered in the event that the skin of a patient has been damaged or has an abnormally high permeability. But the release rate per unit area of system cannot be selected at such a low level that the onset of analgesia is delayed beyond five hours or that adequate dosages are not obtained from reasonably sized systems. In addition to these general design criteria we have discovered certain properties of fentanyl, and its derivatives such as skin permeability and drug binding in the skin which impose additional conflicting design constraints.
According to our invention we have provided methods for the transdermal delivery of fentanyl or its derivatives and transdermal delivery systems for effecting the same, which are suitable for the administration of fentanyl or its derivatives continuously through intact skin for the alleviation of pain.
It is accordingly an object of this invention to provide a method for the continuous transdermal administration of fentanyl or its derivatives.
It is another object of this invention to provide transdermal therapeutic systems usable to administer fentanyl or its derivatives at a substantially constant rate for an extended period of time to produce analgesia.
It is another object of this invention to provide rate limited, duration specified transdermal therapeutic systems for the administration of fentanyl or its derivatives to the systemic circulation.
It is another object of this invention to provide transdermal therapeutic systems for the administration of fentanyl or its derivatives in which the amount of residual drug is minimized.
It is another object of this invention to provide methods and apparatus for the transdermal administration of fentanyl or its derivatives in which the onset of analgesia occurs in a relatively short period of time.